Publications by authors named "Sven Laudi"

35 Publications

Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19.

Nat Biotechnol 2020 Dec 24. Epub 2020 Dec 24.

Center for Digital Health, Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

In coronavirus disease 2019 (COVID-19), hypertension and cardiovascular diseases are major risk factors for critical disease progression. However, the underlying causes and the effects of the main anti-hypertensive therapies-angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)-remain unclear. Combining clinical data (n = 144) and single-cell sequencing data of airway samples (n = 48) with in vitro experiments, we observed a distinct inflammatory predisposition of immune cells in patients with hypertension that correlated with critical COVID-19 progression. ACEI treatment was associated with dampened COVID-19-related hyperinflammation and with increased cell intrinsic antiviral responses, whereas ARB treatment related to enhanced epithelial-immune cell interactions. Macrophages and neutrophils of patients with hypertension, in particular under ARB treatment, exhibited higher expression of the pro-inflammatory cytokines CCL3 and CCL4 and the chemokine receptor CCR1. Although the limited size of our cohort does not allow us to establish clinical efficacy, our data suggest that the clinical benefits of ACEI treatment in patients with COVID-19 who have hypertension warrant further investigation.
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http://dx.doi.org/10.1038/s41587-020-00796-1DOI Listing
December 2020

COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis.

Nat Biotechnol 2020 08 26;38(8):970-979. Epub 2020 Jun 26.

Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Berlin, Germany.

To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls. We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand-receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF. The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19.
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http://dx.doi.org/10.1038/s41587-020-0602-4DOI Listing
August 2020

Clinical Guideline for Treating Acute Respiratory Insufficiency with Invasive Ventilation and Extracorporeal Membrane Oxygenation: Evidence-Based Recommendations for Choosing Modes and Setting Parameters of Mechanical Ventilation.

Respiration 2019;98(4):357-372. Epub 2019 Sep 10.

Department of Anesthesiology and Intensive Care Medicine, University of Leipzig Medical Center, Leipzig, Germany.

For patients with acute respiratory insufficiency, mechanical ("invasive") ventilation is a fundamental therapeutic measure to ensure sufficient gas exchange. Despite decades of strong research efforts, central questions on mechanical ventilation therapy are still answered incompletely. Therefore, many different ventilation modes and settings have been used in daily clinical practice without scientifically sound bases. At the same time, implementation of the few evidence-based therapeutic concepts (e.g., "lung protective ventilation") into clinical practice is still insufficient. The aim of our guideline project "Mechanical ventilation and extracorporeal gas exchange in acute respiratory insufficiency" was to develop an evidence-based decision aid for treating patients with and on mechanical ventilation. It covers the whole pathway of invasively ventilated patients (including indications of mechanical ventilation, ventilator settings, additional and rescue therapies, and liberation from mechanical ventilation). To assess the quality of scientific evidence and subsequently derive recommendations, we applied the Grading of Recommendations, Assessment, Development and Evaluation method. For the first time, using this globally accepted methodological standard, our guideline contains recommendations on mechanical ventilation therapy not only for acute respiratory distress syndrome patients but also for all types of acute respiratory insufficiency. This review presents the two main chapters of the guideline on choosing the mode of mechanical ventilation and setting its parameters. The guideline group aimed that - by thorough implementation of the recommendations - critical care teams may further improve the quality of care for patients suffering from acute respiratory insufficiency. By identifying relevant gaps of scientific evidence, the guideline group intended to support the development of important research projects.
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http://dx.doi.org/10.1159/000502157DOI Listing
September 2020

Mechanical Ventilation and Extracorporeal Membrane Oxygena tion in Acute Respiratory Insufficiency.

Dtsch Arztebl Int 2018 12;115(50):840-847

Board of directors, Ulm University Hospital

Background: Mechanical ventilation is life-saving for patients with acute respiratory insufficiency. In a German prevalence study, 13.6% of patients in intensive care units received mechanical ventilation for more than 12 hours; 20% of these patients received mechanical ventilation as treatment for acute respiratory distress syndrome (ARDS). The new S3 guideline is the first to contain recommendations for the entire process of treatment in these groups of patients (indications, ventilation modes/parameters, ac- companying measures, treatments for refractory impairment of gas exchange, weaning, and follow-up care).

Methods: This guideline was developed according to the GRADE methods. Pertinent publications were identified by a systematic search of the literature, the quality of the evidence was evaluated, a risk/benefit assessment was conducted, and recommendations were issued by interdisciplinary consensus.

Results: Mechanical ventilation is recommended as primary treatment for patients with severe ARDS. In other patient groups, non-in- vasive ventilation can lower mortality. If mechanical ventilation is needed, ventilation modes allowing spontaneous breathing seem beneficial (quality of evidence [QoE]: very low). Protective ventilation (high positive end-expiratory pressure, low tidal volume, limited peak pressure) improve the survival of ARDS patients (QoE: high). If a severe impairment of gas exchange is present, prone posi- tioning lessens mortality (QoE: high). Veno-venous extracorporeal membrane oxygenation (vvECMO) has not unequivocally been shown to improve survival. Early mobilization and weaning protocols can shorten the duration of ventilation (QoE: moderate).

Conclusion: Recommendations for patients undergoing mechanical ventilation include lung-protective ventilation, early sponta- neous breathing and mobilization, weaning protocols, and, for those with severe impairment of gas exchange, prone positioning. It is further recommended that patients with ARDS and refractory impairment of gas exchange should be transferred to an ARDS/ECMO center, where extracorporeal methods should be applied only after application of all other therapeutic options.
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http://dx.doi.org/10.3238/arztebl.2018.0840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375070PMC
December 2018

Hydroxyethyl starch for volume expansion after subarachnoid haemorrhage and renal function: Results of a retrospective analysis.

PLoS One 2018 15;13(2):e0192832. Epub 2018 Feb 15.

Department of Neurosurgery, University Hospital Leipzig, Leipzig, Germany.

Background: Hydroxyethyl starch (HES) was part of "triple-H" therapy for prophylaxis and therapy of vasospasm in patients with subarachnoid haemorrhage (SAH). The European Medicines Agency restricted the use of HES in 2013 due to an increase of renal failure in critically ill patients receiving HES compared to crystalloid fluids. The occurrence of renal insufficiency in patients with SAH due to HES is still uncertain. The purpose of our study was to evaluate whether there was an association with renal impairment in patients receiving HES after subarachnoid haemorrhage.

Methods: Medical records of all non-traumatic SAH patients treated at the Departments of Anaesthesiology and Neurosurgery, University Hospital of Leipzig, Germany, between January 2009 and December 2014 were analysed. Patients received either HES 6% and/or 10% (HES group, n = 183) or exclusively crystalloids for fluid therapy (Crystalloid group, n = 93). Primary outcome was the incidence of acute kidney injury.

Results: The study groups had similar characteristics except for initial SAPS scores, incidence of vasospasm and ICU length of stay. Patients receiving HES fulfilled significantly more often SIRS (systemic inflammatory response syndrome) criteria. 24.6% (45/183) of the patients in the HES group had acute kidney injury (KDIGO 1-3) at any time during their ICU stay compared to 26.9% (25/93) in the crystalloid group (p = 0.679). Only few patients needed renal replacement therapy with no significant difference between groups (Crystalloid group: 4.3%; HES group: 2.2%; p = 0.322). The incidence of vasospasm was increased in the HES group when compared to the crystalloid group (33.9% vs. 17.2%; p = 0.004).

Conclusion: In the presented series of patients with non-traumatic SAH we found no significant association between HES therapy and the incidence of acute kidney injury. Treatment without HES did not worsen patient outcome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192832PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813956PMC
April 2018

The effects of hemoglobin glutamer-200 and iNO on pulmonary vascular tone and arterial oxygenation in an experimental acute respiratory distress syndrome.

Pulm Pharmacol Ther 2018 04 6;49:130-133. Epub 2018 Feb 6.

University of Leipzig, Medical Faculty; Department of Anaesthesiology and Intensive Care Medicine, Liebigstrasse 20, 04103 Leipzig, Germany. Electronic address:

Introduction: Hemoglobin-based oxygen carriers (HBOC) have been developed as an alternative to blood transfusions. Their nitric-oxide-scavenging properties HBOC also induce vasoconstriction. In acute lung injury, an excess of nitric oxide results in a general vasodilation, reducing oxygenation by impairing the hypoxic pulmonary vasoconstriction. Inhaled nitric oxide (iNO) is used to correct the ventilation perfusion mismatch. We hypothesized that the additional use of HBOC might increase this effect. In a rodent model of ARDS we evaluated the combined effect of HBOC and iNO on vascular tone and gas exchange.

Methods: ARDS was induced in anaesthetized Wistar rats by saline lavage and aggressive ventilation. Two groups received either hydroxyethylstarch 10% (HES; n = 10) or the HBOC hemoglobin glutamer-200 (HBOC-200; n = 10) via a central venous infusion. Additionally, both groups received iNO. Monitoring of the right ventricular pressure (RVP) and mean arterial pressure (MAP) was performed with microtip transducers. Arterial oxygenation was measured via arterial blood gas analyses.

Results: Application of HBOC-200 led to a significant increase of MAP and RVP when compared to baseline and to the HES group. This effect was reversed by iNO. The application of HBOC and iNO had no effect on the arterial oxygenation over time. No difference in arterial oxygenation was found between the groups.

Conclusion: Application of HBOC led to an increase of systemic and pulmonary vascular resistance in this animal model of ARDS. The increase in RVP was reversed by iNO. Pulmonary vasoconstriction by hemoglobin glutamer-200 in combination with iNO did not improve arterial oxygenation in ARDS.
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http://dx.doi.org/10.1016/j.pupt.2018.01.009DOI Listing
April 2018

Two-Year Follow-Up After Percutaneous Dilatational Tracheostomy in a Surgical ICU.

Respir Care 2017 Jul 2;62(7):963-969. Epub 2017 May 2.

Department of Anesthesiology and Intensive Care Medicine.

Background: The modalities of tracheostomy for critically ill patients are still controversially discussed. Although the use of percutaneous dilatational tracheostomy (PDT) is generally accepted to be a safe procedure, it is still not considered to be suitable for patients requiring a permanent tracheostomy.

Methods: This was an observational cohort study investigating long-term outcome parameters of PDT. All patients having received a PDT at the interdisciplinary ICU at the University of Leipzig between October 2008 and August 2009 that survived to discharge were asked for consent to participate ( = 103). Baseline data, admitting diagnosis, reasons for tracheostomy, and timing for tracheostomy were recorded. Subjects and medical providers were asked for neurological outcome, adverse events, and personal discomfort related to the tracheostomy. The study period was 2 y from the time of tracheostomy.

Results: Seventy-one subjects were finally included in the survey. Data of 8 subjects (11%) were incomplete. Reasons for tracheostomy were the need for long-term ventilation (42%), weaning (31%), and neurological deficits (27%). No severe adverse events were registered. Sixty-five percent of all subjects could finally be decannulated. Two subjects remained with their initial tracheostomy, and in 5 subjects (7%) tracheostomy was modified to a surgical tracheostomy. Thirty-seven percent of subjects died during the 2 y. Twenty-five of the surviving subjects (35%) had only minor or moderate neurological and psychological deficits. Complaints were mostly connected to swallowing and breathing.

Conclusions: Decannulations after PDT are easily done. Complications after PDT requiring a transformation to a surgical tracheostomy are rare. Elective surgical conversions are not necessary.
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http://dx.doi.org/10.4187/respcare.05290DOI Listing
July 2017

Distributive shock, cardiac arrhythmias and multiple organ failure following surgery of a fourth ventricular epidermoid.

BMJ Case Rep 2016 Mar 31;2016. Epub 2016 Mar 31.

Department of Neurosurgery, University of Leipzig, Medical Faculty, Leipzig, Germany.

A 33-years-old male patient presented with cardiac arrhythmias, acute shock and multiple organ dysfunction after the surgical removal of a massive epidermoid posterior to the brainstem. The patient initially presented with paraesthesia along the right C6 dermatome due to a big tumour at the brain stem. Surgical removal was performed without adverse events and he was transferred to our intensive care unit (ICU) immediately after the operation. Though initially showing a stable postsurgical course he developed cardiac arrhythmias and a state of acute distributive shock with consecutive multi organ failure. Extensive diagnostic measures could not identify a specific cause for this rapid deterioration. However, under carefully monitored symptomatic therapy the patient improved quickly, was extubated 72 h after admission and discharged from the ICU 6 days later. The follow-up did not show any persisting neurological deficits and no evidence of a residual tumour in the MRI-study.
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http://dx.doi.org/10.1136/bcr-2015-214035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840605PMC
March 2016

Two strategies for prevention of cytomegalovirus infections after liver transplantation.

World J Gastroenterol 2016 Mar;22(12):3412-7

Philipp Simon, Max Sasse, Sven Laudi, Udo X Kaisers, Sven Bercker, Department of Anesthesia and Intensive Care Medicine, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.

Aim: To analyze differences in patients' clinical course, we compared two regimes of either preemptive therapy or prophylaxis after liver transplantation.

Methods: This retrospective study was reviewed and approved by the institutional review board of the University of Leipzig. Cytomegalovirus (CMV) prophylaxis with valganciclovir hydrochloride for liver transplant recipients was replaced by a preemptive strategy in October 2009. We retrospectively compared liver transplant recipients 2 years before and after October 2009. During the first period, all patients received valganciclovir daily. During the second period all patients included in the analysis were treated following a preemptive strategy. Outcomes included one year survival and therapeutic intervention due to CMV viremia or infection.

Results: Between 2007 and 2010 n = 226 patients underwent liver transplantation in our center. n = 55 patients were D(+)/R(-) high risk recipients and were excluded from further analysis. A further 43 patients had to be excluded since CMV prophylaxis/preemptive strategy was not followed although there was no clinical reason for the deviation. Of the remaining 128 patients whose data were analyzed, 60 received prophylaxis and 68 were treated following a preemptive strategy. The difference in overall mortality was not significant, nor was it significant for one-year mortality where it was 10% (95%CI: 8%-28%, P = 0.31) higher for the preemptive group. No significant differences in blood count abnormalities or the incidence of sepsis and infections were observed other than CMV. In total, 19 patients (14.7%) received ganciclovir due to CMV viremia and/or infections. Patients who were treated according to the preemptive algorithm had a significantly higher rate risk of therapeutic intervention with ganciclovir [n = 16 (23.5%) vs n = 3 (4.9%), P = 0.003)].

Conclusion: These data suggest that CMV prophylaxis is superior to a preemptive strategy in patients undergoing liver transplantation.
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http://dx.doi.org/10.3748/wjg.v22.i12.3412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806199PMC
March 2016

[Social aspects of emergency calls in the rescue service].

Anaesthesist 2015 Apr;64(4):304-14

Klinik und Poliklinik für Anästhesiologie und Intensivmedizin, Uniklinikum Leipzig, Liebigstr. 20, 04103, Leipzig, Deutschland,

Background: Many missions in the preclinical emergency services seem to be triggered by false indications as defined by the Federal State Rescue Act. These emergency calls are often a result of or associated with social issues. Emergency rescue personnel are confronted with social problems and as a result often feel left alone with the problem.

Aim: This article promotes the understanding of emergency service personnel for the associations between social problems and health. Solution strategies for frequent social emergencies are described.

Material And Methods: This article demonstrates the associations between socioeconomic status, health and disease. Typical indications for missions in which social aspects play an important role are presented and solution strategies for the approach are suggested. A discussion is presented on how to deal with cases of child abuse and domestic violence. Three classical psychiatric problem areas with common social components are explained: psychomotor state of excitation, suicide and alcohol-associated incidents and special attention is paid to danger to third parties and aggressive patients. In addition to the treatment of medical conditions, social problems play an important role particularly for the elderly and chronically ill patients.

Results And Conclusion: Emergency personnel have only limited options for dealing with such problems; however, it is important to be aware of regional structures and non-medical organizations, which might be of help in such situations. These include social services, youth welfare services, crisis interventions teams and social psychiatric services.
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http://dx.doi.org/10.1007/s00101-015-0014-xDOI Listing
April 2015

Restrictive transfusion practice during extracorporeal membrane oxygenation therapy for severe acute respiratory distress syndrome.

Artif Organs 2015 Apr 27;39(4):374-8. Epub 2014 Oct 27.

Department of Anesthesiology and Intensive Care Medicine, University of Leipzig, Leipzig, Germany.

Recommendations concerning the management of hemoglobin levels and hematocrit in patients on extracorporeal membrane oxygenation (ECMO) still advise maintenance of a normal hematocrit. In contrast, current transfusion guidelines for critically ill patients support restrictive transfusion practice. We report on a series of patients receiving venovenous ECMO (vvECMO) for acute respiratory distress syndrome (ARDS) treated according to the restrictive transfusion regimen recommended for critically ill patients. We retrospectively analyzed 18 patients receiving vvECMO due to severe ARDS. Hemoglobin concentrations were kept between 7 and 9 g/dL with a transfusion trigger at 7 g/dL or when physiological transfusion triggers were apparent. We assessed baseline data, hospital mortality, time on ECMO, hemoglobin levels, hematocrit, quantities of packed red blood cells received, and lactate concentrations and compared survivors and nonsurvivors. The overall mortality of all patients on vvECMO was 38.9%. Mean hemoglobin concentration over all patients and ECMO days was 8.30 ± 0.51 g/dL, and hematocrit was 0.25 ± 0.01, with no difference between survivors and nonsurvivors. Mean numbers of given PRBCs showed a trend towards higher quantities in the group of nonsurvivors, but the difference was not significant (1.97 ± 1.47 vs. 0.96 ± 0.76 units; P = 0.07). Mean lactate clearance from the first to the third day was 45.4 ± 28.3%, with no significant difference between survivors and nonsurvivors (P = 0.19). In our cohort of patients treated with ECMO due to severe ARDS, the application of a restrictive transfusion protocol did not result in an increased mortality. Safety and feasibility of the application of a restrictive transfusion protocol in patients on ECMO must further be evaluated in randomized controlled trials.
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http://dx.doi.org/10.1111/aor.12385DOI Listing
April 2015

Characterization of a double-hit murine model of acute respiratory distress syndrome.

Clin Exp Pharmacol Physiol 2014 Oct;41(10):844-53

Department of Anesthesiology and Intensive Care Medicine, University Hospital of Leipzig, Leipzig, Germany.

The aim of the present study was to characterize a murine model of acute respiratory distress syndrome (ARDS) abiding by the Berlin definition of human ARDS and guidelines for animal models of ARDS. To this end, C57BL/6NCrl mice were challenged with lipopolysaccharide (LPS; 15 mg/kg, i.p.) followed 18 h later by injection of oleic acid (OA; 0.12 mL/kg, i.v.). Controls received saline injection at both time points. Haemodynamics were monitored continuously. Arterial blood gas analyses were performed just before and every 30 min after OA challenge. Ninety minutes after OA challenge, the chest of mice was scanned using micro-computed tomography (CT). Cytokine concentrations were measured in plasma samples. Lungs were harvested 90 min after OA challenge for histology, immunohistochemistry, lung weight measurements and tissue cytokine detection. A histological lung injury score was determined. Eighteen hours after LPS challenge, mice exhibited a severe systemic inflammatory response syndrome. Oxygenation declined significantly after OA injections (Pa o2 /Fi o2 283 ± 73 and 256 ± 71 mmHg at 60 and 90 min, respectively; P < 0.001). Bilateral patchy infiltrates were present on the micro-CT scans. Histology revealed parenchymal damage with accumulation of polymorphonuclear neutrophils, intra-alveolar proteinacous debris and few hyaline membranes. The lung wet : dry ratio indicated damage to the alveolar capillary membrane. Cytokine patterns evidenced a severe local and systemic inflammatory state in plasma and lung tissue. In conclusion, the described two-hit model of ARDS shows a pathological picture of ARDS closely mimicking human ARDS according to the Berlin definition and may facilitate interpretation of prospective experimental results.
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http://dx.doi.org/10.1111/1440-1681.12283DOI Listing
October 2014

Lessons learned from excess mortality associated with Klebsiella pneumoniae carbapenemase 2-producing K. pneumoniae in liver transplant recipients.

Liver Transpl 2014 Jun 26;20(6):736-8. Epub 2014 Mar 26.

Division of Infectious Diseases and Tropical Medicine Department of Gastroenterology and Rheumatology, Leipzig University Hospital, Leipzig, Germany.

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http://dx.doi.org/10.1002/lt.23858DOI Listing
June 2014

Is the time right to fight global warming in sepsis?

Crit Care Med 2013 Dec;41(12):2835-6

Department of Anesthesiology and Intensive Care Medicine University of Leipzig Medical Faculty Leipzig, Germany Anesthesiology Services Lowell General Hospital Lowell, MA.

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http://dx.doi.org/10.1097/CCM.0b013e31829cb357DOI Listing
December 2013

Rapid emergence of secondary resistance to gentamicin and colistin following selective digestive decontamination in patients with KPC-2-producing Klebsiella pneumoniae: a single-centre experience.

Int J Antimicrob Agents 2013 Dec 19;42(6):565-70. Epub 2013 Sep 19.

Division of Infectious Diseases and Tropical Medicine, Department of Gastroenterology and Rheumatology, Leipzig University Hospital, Liebigstr. 20, D-04103 Leipzig, Germany. Electronic address:

After a single patient was transferred to Leipzig University Hospital from a hospital in Rhodes, Greece, the hospital experienced the largest outbreak due to a KPC-2-producing Klebsiella pneumoniae (KPC-2-KP) strain thus far observed in Germany. Ninety patients hospitalised between July 2010 and October 2012 were affected. In an attempt to eliminate KPC-2-KP from their digestive tracts, 14 consecutive patients (16%) were treated with a short course (7 days) of selective digestive decontamination (SDD), employing colistin (1 million units q.i.d.) and gentamicin (80 mg q.i.d.) as oral solutions, and applying colistin/gentamicin gel (0.5 g) to the oral cavity. In a retrospective analysis, these 14 SDD patients were compared with the remaining 76 patients harbouring KPC-2-KP. KPC-2-KP carrier status was followed in all 14 SDD patients by submitting stool samples to KPC-specific PCR. The mean follow-up period was 48 days (range 12-103 days). Successful elimination of KPC-2-KP was defined as a minimum of three consecutive negative PCR test results separated by ≥48 h each. Decolonisation of KPC-2-KP was achieved in 6/14 patients (43%) after a mean of 21 days (range 12-40 days), but was also observed in 23/76 (30%) of the non-SDD controls (P = 0.102). SDD treatment resulted in the development of secondary resistance to colistin (19% increase in resistance rate) and gentamicin (45% increase) in post-treatment isolates. In the control group, no secondary resistance occurred. We conclude that the SDD protocol applied in this study was not sufficiently effective for decolonisation and was associated with resistance development.
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http://dx.doi.org/10.1016/j.ijantimicag.2013.08.008DOI Listing
December 2013

Imaging of the brain serotonin transporters (SERT) with 18F-labelled fluoromethyl-McN5652 and PET in humans.

Eur J Nucl Med Mol Imaging 2012 Jun 17;39(6):1001-11. Epub 2012 Feb 17.

Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.

Purpose: [(11)C]DASB is currently the most frequently used highly selective radiotracer for visualization and quantification of central SERT. Its use, however, is hampered by the short half-life of (11)C, the moderate cortical test-retest reliability, and the lack of quantifying endogenous serotonin. Labelling with (18)F allows in principle longer acquisition times for kinetic analysis in brain tissue and may provide higher sensitivity. The aim of our study was to firstly use the new highly SERT-selective (18)F-labelled fluoromethyl analogue of (+)-McN5652 ((+)-[(18)F]FMe-McN5652) in humans and to evaluate its potential for SERT quantification.

Methods: The PET data from five healthy volunteers (three men, two women, age 39 ± 10 years) coregistered with individual MRI scans were semiquantitatively assessed by volume-of-interest analysis using the software package PMOD. Rate constants and total distribution volumes (V (T)) were calculated using a two-tissue compartment model and arterial input function measurements were corrected for metabolite/plasma data. Standardized uptake region-to-cerebellum ratios as a measure of specific radiotracer accumulation were compared with those of a [(11)C]DASB PET dataset from 21 healthy subjects (10 men, 11 women, age 38 ± 8 years).

Results: The two-tissue compartment model provided adequate fits to the data. Estimates of total distribution volume (V (T)) demonstrated good identifiability based on the coefficients of variation (COV) for the volumes of interest in SERT-rich and cortical areas (COV V (T) <10%). Compared with [(11)C]DASB PET, there was a tendency to lower mean uptake values in (+)-[(18)F]FMe-McN5652 PET; however, the standard deviation was also somewhat lower. Altogether, cerebral (+)-[(18)F]FMe-McN5652 uptake corresponded well with the known SERT distribution in humans.

Conclusion: The results showed that (+)-[(18)F]FMe-McN5652 is also suitable for in vivo quantification of SERT with PET. Because of the long half-life of (18)F, the widespread use within a satellite concept seems feasible.
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http://dx.doi.org/10.1007/s00259-012-2078-zDOI Listing
June 2012

Incidental transarterial placement of a dialysis catheter into the femoral vein.

Ann Card Anaesth 2012 Jan-Mar;15(1):67-8

Department of Anaesthesiology and Intensive Care Medicine, University of Leipzig, Medical Faculty, 04103 Leipzig, Germany.

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http://dx.doi.org/10.4103/0971-9784.91487DOI Listing
May 2012

Impact of the MELD allocation after its implementation in liver transplantation.

Scand J Gastroenterol 2011 Jul 28;46(7-8):941-8. Epub 2011 Mar 28.

Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Universitätsklinikum Leipzig, Leipzig, Germany.

Objective: On 16 December 2006, most Eurotransplant countries changed waiting time oriented liver allocation policy to the urgency oriented Model for End-stage Liver Disease (MELD) system. There are limited data on the effects of this policy change within the Eurotransplant community.

Patients And Methods: A total of 154 patients who had undergone deceased donor liver transplantation (LT) were retrospectively analyzed in three time periods: period A (1-year pre-MELD, n = 42) versus period B (1-year post-MELD, n = 52) versus period C (2 years after MELD implementation, n = 60).

Results: The median MELD score at the time of LT increased from 16.3 points in period A to 22.4 and 20.4 in periods B and C, respectively (p = 0.007). Waitlist mortality decreased from 18.4% in period A to 10.4% and 9.4% in periods B and C, respectively (p = 0.015). Three-month mortality did not change significantly (10% each for periods A, B and C). One-year survival was 84% for the MELD 6-19 group compared with 81% in the MELD 20-29 group and 74% in the MELD ≥30 group (p = 0.823). Analyzing MELD score and previously described prognostic scores [i.e. survival after liver transplantation (SALT) score and donor-MELD (D-MELD) score] with regard to 1-year survival, only a high risk SALT score was predictive (p = 0.038). In our center, 2 years after implementation of the MELD system, waitlist mortality decreased, while 90-day mortality did not change significantly.

Conclusion: Up to now, only the SALT score proved to be of prognostic relevance post-transplant.
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http://dx.doi.org/10.3109/00365521.2011.568521DOI Listing
July 2011

Unusual left-ventricular malposition of a pulmonary artery catheter.

Am J Respir Crit Care Med 2011 Feb;183(4):552

Department of Anesthesiology and Intensive Care Medicine, University of Leipzig, Medical Faculty, Leipzig, Germany.

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http://dx.doi.org/10.1164/rccm.201008-1292IMDOI Listing
February 2011

Neprilysin null mice develop exaggerated pulmonary vascular remodeling in response to chronic hypoxia.

Am J Pathol 2009 Mar;174(3):782-96

Cardiovascular Pulmonary Research Laboratory; B-133, University of Colorado Denver, 12700 E. 19 Ave, Aurora, CO 80046, USA.

Neprilysin is a transmembrane metalloendopeptidase that degrades neuropeptides that are important for both growth and contraction. In addition to promoting carcinogenesis, decreased levels of neprilysin increases inflammation and neuroendocrine cell hyperplasia, which may predispose to vascular remodeling. Early pharmacological studies showed a decrease in chronic hypoxic pulmonary hypertension with neprilysin inhibition. We used a genetic approach to test the alternate hypothesis that neprilysin depletion increases chronic hypoxic pulmonary hypertension. Loss of neprilysin had no effect on baseline airway or alveolar wall architecture, vessel density, cardiac function, hematocrit, or other relevant peptidases. Only lung neuroendocrine cell hyperplasia and a subtle neuropeptide imbalance were found. After chronic hypoxia, neprilysin-null mice exhibited exaggerated pulmonary hypertension and striking increases in muscularization of distal vessels. Subtle thickening of proximal media/adventitia not typically seen in mice was also detected. In contrast, adaptive right ventricular hypertrophy was less than anticipated. Hypoxic wild-type pulmonary vessels displayed close temporal and spatial relationships between decreased neprilysin and increased cell growth. Smooth muscle cells from neprilysin-null pulmonary arteries had increased proliferation compared with controls, which was decreased by neprilysin replacement. These data suggest that neprilysin may be protective against chronic hypoxic pulmonary hypertension in the lung, at least in part by attenuating the growth of smooth muscle cells. Lung-targeted strategies to increase neprilysin levels could have therapeutic benefits in the treatment of this disorder.
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http://dx.doi.org/10.2353/ajpath.2009.080345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665740PMC
March 2009

[Inhaled nitric oxide for rescue treatment of refractory hypoxemia in ARDS patients].

Anasthesiol Intensivmed Notfallmed Schmerzther 2008 Nov 18;43(11-12):778-83; quiz 784. Epub 2008 Nov 18.

Department of Anesthesiology and Intensive Care Medicine, University of Leipzig, Leipzig, Germany.

The acute respiratory distress syndrome (ARDS) is characterized by a maldistribution of pulmonary blood flow towards non-ventilated atelectatic lung areas being the main reason for intrapulmonary right-to-left shunt with the consequence of severe arterial hypoxemia. The application of inhaled nitric oxide (iNO) is a therapeutic option to selectively influence pulmonary blood flow in order to improve arterial oxygenation and to decrease pulmonary artery pressure without relevant systemic side effects. Although randomized controlled trials demonstrated no survival benefit in patient populations covering the entire severity range of acute lung injury, iNO represents a feasible rescue treatment for ARDS patients with severe refractory hypoxemia and is, therefore, an important option for ARDS therapy in specialized centers.
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http://dx.doi.org/10.1055/s-0028-1104618DOI Listing
November 2008

Murine pulmonary response to chronic hypoxia is strain specific.

Exp Lung Res 2008 Aug;34(6):313-23

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA.

Information concerning the effects of genetic variation between different background strains on hemodynamic, morphometric, and gene expression response to hypoxia would be useful. Three strains of mice were kept in hypoxia and phenotyped followed by gene profiling analysis. Among the variables examined, hematocrit, right heart muscularization, and right ventricular systolic pressure showed a strain-specific effect. Increased gene expression of inflammatory, muscle, and angiogenesis genes were seen in all strains, though the specific genes changed varied among groups. These results suggest that different strains use different gene expression mechanisms to adapt to the challenge of chronic hypoxia, resulting in modified phenotypic changes.
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http://dx.doi.org/10.1080/01902140802093204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769701PMC
August 2008

Chronic renal dysfunction following liver transplantation.

Clin Transplant 2008 May-Jun;22(3):333-40. Epub 2008 Mar 12.

Department of General and Transplantation Surgery, Charité, Campus Virchow, Berlin, Germany.

With most of the immunosuppressive protocols consisting of calcineurin inhibitors (CI), nephrotoxicity has become a major long-term complication often compromising outcome. In a single-center retrospective study, we reviewed 1173 liver transplantations to identify variables indicative for the occurrence of chronic renal dysfunction (CRD) (defined as > or = 1 episode of serum creatinine increase > or = 1.8 mg/dL > or = 2 wk). Chronic renal dysfunction was found in 137 (11.7%) of all transplants [82 (7%) early (after 3-12 months), 55 (4.7%) late-onset (> 12 months)]. Compared to 5-/10-yr survival rates in non-CRD transplants (84/74%) survival was significantly decreased in early (66/46%), but unchanged in late-onset CRD (98/86%). Rates of alcoholic cirrhosis and prior renal dysfunction were significantly increased in patients with CRD. In a multivariate logistic regression analysis, only cyclosporine A (CyA) as immunosuppression remained an independent risk factor. No correlations to age, gender, rejection/retransplantation or diabetes were found. Surprisingly, renal function (creatinine) showed no difference between patients on CI monotherapy (FK/CyA) compared to those who had mycophenolate mofetil (MMF) added. In liver transplantation, early onset CRD significantly compromises survival. CyA-based immunosuppression appears to have a stronger impact than FK. The fact that patients with long-term severe chronic renal dysfunction failed to improve under MMF rescue therapy emphasizes the importance of new diagnostic strategies to earlier identify at-risk patients.
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http://dx.doi.org/10.1111/j.1399-0012.2008.00806.xDOI Listing
July 2008

Inhalation of the ETA receptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction.

Am J Physiol Regul Integr Comp Physiol 2008 Feb 12;294(2):R601-5. Epub 2007 Dec 12.

Klinik und Poliklinik fuer Anaesthesiologie und Intensivtherapie, Universitaetsklinikum Leipzig, Liebigstrasse 20, Leipzig, Germany.

Endogenous endothelin (ET)-1 modulates hypoxic pulmonary vasoconstriction (HPV). Accordingly, intravenously applied ET(A) receptor antagonists reduce HPV, but this is accompanied by systemic vasodilation. We hypothesized that inhalation of an ET(A) receptor antagonist might act selectively on the pulmonary vasculature and investigated the effects of aerosolized LU-135252 in an experimental model of HPV. Sixteen piglets (weight: 25 +/- 1 kg) were anesthetized and mechanically ventilated at an inspiratory oxygen fraction (Fi(O(2))) of 0.3. After 1 h of hypoxia at Fi(O(2)) 0.15, animals were randomly assigned either to receive aerosolized LU-135252 as bolus (0.3 mg/kg for 20 min; n = 8, LU group), or to receive aerosolized saline (n = 8, controls). In all animals, hypoxia significantly increased mean pulmonary arterial pressure (32 +/- 1 vs. 23 +/- 1 mmHg; P < 0.01; means +/- SE) and increased arterial plasma ET-1 (0.52 +/- 0.04 vs. 0.37 +/- 0.05 fmol/ml; P < 0.01) compared with mild hyperoxia at Fi(O(2)) 0.3. Inhalation of LU-135252 induced a significant and sustained decrease in mean pulmonary arterial pressure compared with controls (LU group: 27 +/- 1 mmHg; controls: 32 +/- 1 mmHg; values at 4 h of hypoxia; P < 0.01). In parallel, mean systemic arterial pressure and cardiac output remained stable and were not significantly different from control values. Consequently, in our experimental model of HPV, the inhaled ET(A) receptor antagonist LU-135252 induced selective pulmonary vasodilation without adverse systemic hemodynamic effects.
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http://dx.doi.org/10.1152/ajpregu.00739.2007DOI Listing
February 2008

[Therapeutic options for patients with acute lung injury].

Anasthesiol Intensivmed Notfallmed Schmerzther 2007 Nov;42(11):794-9

Klinik und Poliklinik für Anästhesiologie und Intensivtherapie des Universitätsklinikums Leipzig.

The treatment of acute lung injury is one of the most challenging tasks in intensive care medicine. Conventional therapeutic options cover lung protective mechanical ventilation with low tidal volumes and adequate PEEP, restrictive fluid management, prone positioning, and early recruitment maneuvers. These options should be used in parallel and should be accompanied by a suitable anti-infective therapy. In cases of refractory hypoxemia, inhaled nitric oxide offers in most patients a successful rescue option. In specialized centers the application of ECMO remains as a final ultima ratio.
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http://dx.doi.org/10.1055/s-2007-1003592DOI Listing
November 2007

Comparison of lung proteome profiles in two rodent models of pulmonary arterial hypertension.

Proteomics 2007 Jul;7(14):2469-78

University of Leipzig Medical Faculty, Department of Anesthesiology and Intensive Care Medicine, Leipzig, Germany.

We studied the lung proteome changes in two widely used models of pulmonary arterial hypertension (PAH): monocrotaline (MCT) injection and chronic hypoxia (CH); untreated rats were used as controls (n = 6/group). After 28 days, invasive right ventricular systolic pressure (RVSP) was measured. Lungs were immunostained for alpha-smooth muscle actin (alphaSMA). 2-DE (n = 4/group) followed by nano-LC-MS/MS was applied for protein identification. Western blotting was used additionally if possible. RVSP was significantly increased in MCT- and CH-rats (MCT 62.5 +/- 4.4 mmHg, CH 62.2 +/- 4.1 mmHg, control 25.0 +/- 1.7 mmHg, p<0.001). This was associated with an increase of alphaSMA positive vessels. In both groups, there was a significantly increased expression of proteins associated with the contractile apparatus (diphosphoHsp27 (p<0.001), Septin2 (p<0.001), F-actin capping protein (p<0.01), and tropomyosin beta (p<0.02)). In CH, proteins of the nitric oxide (Hsc70; p = 0.002), carbon monoxide (biliverdin reductase; p = 0.005), and vascular endothelial growth factor (VEGF) pathway (annexin 3; p<0.001) were significantly increased. In MCT, proteins involved in serotonin synthesis (14-3-3; p = 0.02), the enhanced unfolded protein response (ERp57; p = 0.02), and intracellular chloride channels (CLIC 1; p = 0.002) were significantly elevated. Therefore, MCT- and CH-induced vasoconstriction and remodeling seemed to be mediated via different signaling pathways. These differences should be considered in future studies using either PAH model.
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http://dx.doi.org/10.1002/pmic.200600848DOI Listing
July 2007